Effects of NMDA receptor glycine recognition site antagonism on cerebral metabolic rate for glucose and cerebral blood flow in the conscious rat.
Glycine is a requisite cofactor for glutamatergic activation of the N-methyl-D-aspartate (NMDA) receptor. Antagonism of glutamate at the NMDA receptor has been shown to cause substantial changes in regional cerebral metabolic rate for glucose utilization (CMRglu) and blood flow (CBF). This study examined CMRglu and CBF changes caused by antagonism of glycine at the NMDA receptor recognition site. Rats were anesthetized with halothane and vascular access was obtained. The animals were then awakened. One hour later, either vehicle (control) or ACEA 1021 (5 mg/kg followed by 3.5 mg x kg(-1) x h(-1) or 10 mg/kg followed by 7 mg x kg(-1) x h(-1)) was infused intravenously. CMRglu and CBF were then determined. Autoradiographic analysis of 25 regions revealed effects of ACEA 1021 on CMRglu in the frontal, sensory, parietal and auditory cortices and the anteroventral and subthalamic nuclei. These changes deviated less than 15% from control. Effects on CBF were also small. The CMRglu and CBF effects of ACEA 1021 are substantially less than those previously observed for either competitive or non-competitive glutamate NMDA antagonists. We conclude that inhibition of the NMDA glycine recognition site has little or no effect on CMRglu or CBF at the doses examined. This is consistent with the absence of psychotomimetic effects observed for this class of drugs.
Morimoto
Y
Y
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Wu
B
B
Bart
R D
RD
Morimoto
Y
Y
Pearlstein
R D
RD
Warner
D S
DS
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018009:Receptors, Glycine; C092062:licostinel; D005947:Glucose